Breast cancers are divided into subtypes based on whether they express estrogen receptor, progesterone receptor and Her2/neu. Before cancer treatment is commenced, it is important to identify patient's cancer subtype because some drugs target cancer cells that express estrogen receptor, while other drugs target cancer cells that express other receptors. The HER2/neu gene has been implicated in mammary tumorigenesis, tumor growth and metastasis. HER2/neu is amplified in 20-30% of human breast cancers and the HER2-positive subtype of breast cancer is associated with aggressive metastatic disease. (Korkaya et al. 2008. Oncogene). The instant invention may be helpful in treating HER2-positive breast cancers by providing new compositions and methods that can be used for eliminating HER2-positive breast cancer cells.
Recently a new subtype of breast cancer cells has been identified. These cancer cells are called triple-negative breast cancer cells because they do not express estrogen receptor, progesterone receptor or Her2/neu. (Dent et al. 2007. Clinical Cancer Research 13: 4429-4434). According to Cancer Research UK (2007), triple-negative breast cancer cases make up approximately 15% of all breast cancer cases. In comparison to other known breast cancer subtypes, the triple-negative subtype is more aggressive, less responsive to standard treatment and is associated with poorer overall patient prognosis. (Dent et al. 2007. Clinical Cancer Research 13: 4429-4434). Thus, there remains the need for compositions and methods to diagnose and treat triple-negative breast cancer patients.
Recent studies suggest that a wide variety of cancers, including breast cancer, arise from a small subset of cancer stem cells (CSCs) through deregulation of self-renewal pathways. It has been reported that a sub-population of breast cancer cells with stem cell-like characteristics is CD44 and CD133 positive, CD24 negative and expresses aldehyde dehydrogenase 1 (ALDH1). (Crocker et al. 2008. J Cell Mol Med). There remains the need for compositions and methods that identify and eradicate a sub-population of breast cancer cells with stem cell-like characteristics.
Prolactin (“PRL”) is a 23-kDa neuroendocrine hormone which is structurally related to growth hormone and, to a lesser degree, to members of the interleukin family (Reynolds et al., 1997, Endocrinol. 138:5555-5560, Cunningham et al., 1990, Science 247:1461-1465; Wells et al., 1993, Recent Prog. Horm. Res. 48:253-275). Prolactin receptors are present in the mammary glands, ovaries, pituitary glands, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle, skin and areas of the central nervous system. Mancini T. (2008), “Hyperprolactinemia and Prolactinomas,” Endocrinology & Metabolism Clinics of North America 37: 67. When prolactin binds to its receptor it causes it to dimerize with another prolactin receptor, which results in the activation of Janus kinase 2, a tyrosine kinase that initiates the JAK-STAT pathway. The activation of the prolactin receptor also results in the activation of mitogen-activated protein kinases and Src kinase mitogen. Mancini, T. (2008). “Hyperprolactinemia and Prolactinomas,” Endocrinology & Metabolism Clinics of North America 37: 67. “Prolactin receptor antagonist” refers to a form of prolactin that interferes with the prolactin signaling pathway. Such prolactin receptor antagonists have been previously described in US Patent Application 2007/0060520 to inventors W. Chen and T. Wagner.